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For:	Li MK, Crawford JM. The pathology of cholestasis. Semin Liver Dis 2004;24:21-42. [PMID: 15085484 DOI: 10.1055/s-2004-823099] [Citation(s) in RCA: 112] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]

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Cited by Other Article(s)

Carolina E, Kuse Y, Okumura A, Aoshima K, Tadokoro T, Matsumoto S, Kanai E, Okumura T, Kasai T, Yamabe S, Nishikawa Y, Yamaguchi K, Furukawa Y, Tanimizu N, Taniguchi H. Generation of human iPSC-derived 3D bile duct within liver organoid by incorporating human iPSC-derived blood vessel. Nat Commun 2024;15:7424. [PMID: 39198465 PMCID: PMC11358266 DOI: 10.1038/s41467-024-51487-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Accepted: 08/06/2024] [Indexed: 09/01/2024] Open

Affiliation(s)

Erica Carolina Division of Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan
Yoshiki Kuse Division of Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
Ayumu Okumura Division of Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan
Kenji Aoshima Division of Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan
Tomomi Tadokoro Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Kanagawa, Japan
Shinya Matsumoto Division of Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
Eriko Kanai Division of Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
Takashi Okumura Division of Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
Toshiharu Kasai Division of Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
Souichiro Yamabe Division of Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan
Yuji Nishikawa Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
Kiyoshi Yamaguchi Division of Clinical Genome Research, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
Yoichi Furukawa Division of Clinical Genome Research, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
Naoki Tanimizu Division of Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Hideki Taniguchi Division of Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Kanagawa, Japan.

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Tang G, Nierath WF, Leitner E, Xie W, Revskij D, Seume N, Zhang X, Ehlers L, Vollmar B, Zechner D. Comparing animal well-being between bile duct ligation models. PLoS One 2024;19:e0303786. [PMID: 38950046 PMCID: PMC11216573 DOI: 10.1371/journal.pone.0303786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Accepted: 05/01/2024] [Indexed: 07/03/2024] Open

Abstract

A prevailing animal model currently used to study severe human diseases like obstructive cholestasis, primary biliary or sclerosing cholangitis, biliary atresia, and acute liver injury is the common bile duct ligation (cBDL). Modifications of this model include ligation of the left hepatic bile duct (pBDL) or ligation of the left bile duct with the corresponding left hepatic artery (pBDL+pAL). Both modifications induce cholestasis only in the left liver lobe. After induction of total or partial cholestasis in mice, the well-being of these animals was evaluated by assessing burrowing behavior, body weight, and a distress score. To compare the pathological features of these animal models, plasma levels of liver enzymes, bile acids, bilirubin, and within the liver tissue, necrosis, fibrosis, inflammation, as well as expression of genes involved in the synthesis or transport of bile acids were assessed. The survival rate of the animals and their well-being was comparable between pBDL+pAL and pBDL. However, surgical intervention by pBDL+pAL caused confluent necrosis and collagen depositions at the edge of necrotic tissue, whereas pBDL caused focal necrosis and fibrosis in between portal areas. Interestingly, pBDL animals had a higher survival rate and their well-being was significantly improved compared to cBDL animals. On day 14 after cBDL liver aspartate, as well as alanine aminotransferase, alkaline phosphatase, glutamate dehydrogenase, bile acids, and bilirubin were significantly elevated, but only glutamate dehydrogenase activity was increased after pBDL. Thus, pBDL may be primarily used to evaluate local features such as inflammation and fibrosis or regulation of genes involved in bile acid synthesis or transport but does not allow to study all systemic features of cholestasis. The pBDL model also has the advantage that fewer mice are needed, because of its high survival rate, and that the well-being of the animals is improved compared to the cBDL animal model.

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Xin X, Jian J, Fan X, Qi B, Zhao Y, Lv W, Zhao Y, Zhao X, Hu C. Multiscale X-ray phase-contrast CT unveils the evolution of bile infarct in obstructive biliary disease. Commun Biol 2024;7:490. [PMID: 38654111 PMCID: PMC11039475 DOI: 10.1038/s42003-024-06185-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Accepted: 04/11/2024] [Indexed: 04/25/2024] Open

Guerrero L, Vindel-Alfageme J, Hierro L, Stark L, Vicent D, Sorzano CÓS, Corrales FJ. Discrimination of Etiologically Different Cholestasis by Modeling Proteomics Datasets. Int J Mol Sci 2024;25:3684. [PMID: 38612495 PMCID: PMC11011353 DOI: 10.3390/ijms25073684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 03/22/2024] [Accepted: 03/24/2024] [Indexed: 04/14/2024] Open

Crawford JM, Bioulac-Sage P, Hytiroglou P. Structure, Function and Responses to Injury. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:1-95. [DOI: 10.1016/b978-0-7020-8228-3.00001-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]

Liu H, Wang X, Deng H, Huang H, Liu Y, Zhong Z, Shen L, Cao S, Ma X, Zhou Z, Chen D, Peng G. Integrated Transcriptome and Metabolomics to Reveal the Mechanism of Adipose Mesenchymal Stem Cells in Treating Liver Fibrosis. Int J Mol Sci 2023;24:16086. [PMID: 38003277 PMCID: PMC10671340 DOI: 10.3390/ijms242216086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 11/01/2023] [Accepted: 11/06/2023] [Indexed: 11/26/2023] Open

Affiliation(s)

Haifeng Liu Department of Veterinary Surgery, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (H.L.); (X.W.); (H.D.); (H.H.); (L.S.); (S.C.); (X.M.); (Y.L.); (Z.Z.); (Z.Z.)
Xinmiao Wang Department of Veterinary Surgery, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (H.L.); (X.W.); (H.D.); (H.H.); (L.S.); (S.C.); (X.M.); (Y.L.); (Z.Z.); (Z.Z.)
Hongchuan Deng Department of Veterinary Surgery, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (H.L.); (X.W.); (H.D.); (H.H.); (L.S.); (S.C.); (X.M.); (Y.L.); (Z.Z.); (Z.Z.)
Haocheng Huang Department of Veterinary Surgery, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (H.L.); (X.W.); (H.D.); (H.H.); (L.S.); (S.C.); (X.M.); (Y.L.); (Z.Z.); (Z.Z.)
Yifan Liu Department of Veterinary Surgery, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (H.L.); (X.W.); (H.D.); (H.H.); (L.S.); (S.C.); (X.M.); (Y.L.); (Z.Z.); (Z.Z.)
Zhijun Zhong Department of Veterinary Surgery, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (H.L.); (X.W.); (H.D.); (H.H.); (L.S.); (S.C.); (X.M.); (Y.L.); (Z.Z.); (Z.Z.)
Liuhong Shen Department of Veterinary Surgery, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (H.L.); (X.W.); (H.D.); (H.H.); (L.S.); (S.C.); (X.M.); (Y.L.); (Z.Z.); (Z.Z.)
Suizhong Cao Department of Veterinary Surgery, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (H.L.); (X.W.); (H.D.); (H.H.); (L.S.); (S.C.); (X.M.); (Y.L.); (Z.Z.); (Z.Z.)
Xiaoping Ma Department of Veterinary Surgery, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (H.L.); (X.W.); (H.D.); (H.H.); (L.S.); (S.C.); (X.M.); (Y.L.); (Z.Z.); (Z.Z.)
Ziyao Zhou Department of Veterinary Surgery, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (H.L.); (X.W.); (H.D.); (H.H.); (L.S.); (S.C.); (X.M.); (Y.L.); (Z.Z.); (Z.Z.)
Dechun Chen College of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu 610041, China
Guangneng Peng Department of Veterinary Surgery, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (H.L.); (X.W.); (H.D.); (H.H.); (L.S.); (S.C.); (X.M.); (Y.L.); (Z.Z.); (Z.Z.)

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Liao S, Fu X, Huang J, Wang Y, Lu Y, Zhou S. Suppression of SIRT1/FXR signaling pathway contributes to oleanolic acid-induced liver injury. Toxicol Appl Pharmacol 2023;467:116509. [PMID: 37028458 DOI: 10.1016/j.taap.2023.116509] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 02/21/2023] [Accepted: 04/02/2023] [Indexed: 04/08/2023]

Chen PC, Hsu CP, Wang SY, Wu TY, Lin YJ, Chen YT, Hsu SH. miR-194 Up-Regulates Cytochrome P450 Family 7 Subfamily A Member 1 Expression via β-Catenin Signaling and Aggravates Cholestatic Liver Diseases. THE AMERICAN JOURNAL OF PATHOLOGY 2023:S0002-9440(23)00058-5. [PMID: 36868469 DOI: 10.1016/j.ajpath.2023.02.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 02/04/2023] [Accepted: 02/15/2023] [Indexed: 03/05/2023]

Leow WQ, Chan AWH, Mendoza PGL, Lo R, Yap K, Kim H. Non-alcoholic fatty liver disease: the pathologist's perspective. Clin Mol Hepatol 2023;29:S302-S318. [PMID: 36384146 PMCID: PMC10029955 DOI: 10.3350/cmh.2022.0329] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 11/09/2022] [Accepted: 11/10/2022] [Indexed: 11/17/2022] Open

Comerford SA, Hinnant EA, Chen Y, Hammer RE. Hepatic ribosomal protein S6 (Rps6) insufficiency results in failed bile duct development and loss of hepatocyte viability; a ribosomopathy-like phenotype that is partially p53-dependent. PLoS Genet 2023;19:e1010595. [PMID: 36656901 PMCID: PMC9888725 DOI: 10.1371/journal.pgen.1010595] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 01/31/2023] [Accepted: 12/26/2022] [Indexed: 01/20/2023] Open

Abstract

Defective ribosome biogenesis (RiBi) underlies a group of clinically diverse human diseases collectively known as the ribosomopathies, core manifestations of which include cytopenias and developmental abnormalities that are believed to stem primarily from an inability to synthesize adequate numbers of ribosomes and concomitant activation of p53. The importance of a correctly functioning RiBi machinery for maintaining tissue homeostasis is illustrated by the observation that, despite having a paucity of certain cell types in early life, ribosomopathy patients have an increased risk for developing cancer later in life. This suggests that hypoproliferative states trigger adaptive responses that can, over time, become maladaptive and inadvertently drive unchecked hyperproliferation and predispose to cancer. Here we describe an experimentally induced ribosomopathy in the mouse and show that a normal level of hepatic ribosomal protein S6 (Rps6) is required for proper bile duct development and preservation of hepatocyte viability and that its insufficiency later promotes overgrowth and predisposes to liver cancer which is accelerated in the absence of the tumor-suppressor PTEN. We also show that the overexpression of c-Myc in the liver ameliorates, while expression of a mutant hyperstable form of p53 partially recapitulates specific aspects of the hepatopathies induced by Rps6 deletion. Surprisingly, co-deletion of p53 in the Rps6-deficient background fails to restore biliary development or significantly improve hepatic function. This study not only reveals a previously unappreciated dependence of the developing liver on adequate levels of Rps6 and exquisitely controlled p53 signaling, but suggests that the increased cancer risk in ribosomopathy patients may, in part, stem from an inability to preserve normal tissue homeostasis in the face of chronic injury and regeneration.

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Quelhas P, Jacinto J, Cerski C, Oliveira R, Oliveira J, Carvalho E, dos Santos J. Protocols of Investigation of Neonatal Cholestasis-A Critical Appraisal. Healthcare (Basel) 2022;10:2012. [PMID: 36292464 PMCID: PMC9602084 DOI: 10.3390/healthcare10102012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 10/06/2022] [Accepted: 10/08/2022] [Indexed: 11/04/2022] Open

Wang C, Ma C, Fu K, Liu Y, Gong L, Peng C, Li Y. Hepatoprotective effect of phillygenin on carbon tetrachloride-induced liver fibrosis and its effects on short chain fatty acid and bile acid metabolism. JOURNAL OF ETHNOPHARMACOLOGY 2022;296:115478. [PMID: 35716920 DOI: 10.1016/j.jep.2022.115478] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 05/17/2022] [Accepted: 06/14/2022] [Indexed: 06/15/2023]

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE

Forsythiae fructus, the dried fruit of Oleaceae plant Forsythia suspensa (Thunb.) Vahl, is a traditional Chinese medicine widely used in clinical practice and has a variety of pharmacological activities, such as anti-inflammation, antioxidation, and hepatoprotection.

AIM OF THE STUDY

Phillygenin (PHI), an important fingerprint lignan component of Forsythiae fructus, has prominent hepatoprotective, anti-inflammatory and antioxidant effects. Previously, it was shown that PHI could exert anti-fibrotic effects by modulating inflammation and gut microbiota. Therefore, given the important roles of SCFAs and BAs in the development of liver fibrosis, as well as their close links with gut microbiota, we aimed to determine the protective effects of PHI on carbon tetrachloride (CCl₄)-induced liver fibrosis and its effects on the metabolism of SCFAs and BAs based on metabolomics.

MATERIALS AND METHODS

In C57BL/6J mice, liver fibrosis model was established by intraperitoneal injection of olive oil containing 10% CCl₄ for 4 weeks. Firstly, the mouse liver tissues were subjected to histological analysis and biochemical index assay to evaluate the protective effect of PHI on CCl₄-induced liver fibrosis. Subsequently, the effects of PHI on the metabolism of SCFAs and BAs in CCl₄-induced liver fibrosis mice were determined using gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS) for metabolomics analysis. Finally, the levels of the closely related proteins and genes were detected by immunohistochemistry and real-time quantitative polymerase chain reaction (RT-qPCR) to explore the underlying mechanisms of the protective effect of PHI on CCl₄-induced liver fibrosis.

RESULTS

The histological analysis and the determination of relevant biochemical indexes of liver tissues showed that PHI could attenuate CCl₄-induced liver fibrosis. The metabolomic analysis on SCFAs showed that PHI could promote SCFA production in the gut of mice with CCl₄-induced liver fibrosis, especially acetic acid, propionic acid and butyric acid. It has been reported that the increased production of SCFAs was possibly beneficial to health. The metabolomic analysis on BAs found that PHI could restore the disturbance of BA metabolism in mice with CCl₄-induced liver fibrosis. The immunohistochemistry and RT-qPCR results confirmed that PHI could ameliorate intestinal epithelial barrier disruption, and reverse the expression of BA metabolism-related genes in mice with CCl₄-induced liver fibrosis.

CONCLUSIONS

Promoting the production of SCFAs in the gut and restoring the disturbance of BA metabolism may be the potential mechanisms by which PHI alleviated CCl₄-induced liver fibrosis.

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Richter B, Sänger C, Mussbach F, Scheuerlein H, Settmacher U, Dahmen U. Species specific morphological alterations in liver tissue after biliary occlusion in rat and mouse: Similar but different. PLoS One 2022;17:e0271975. [PMID: 35881613 PMCID: PMC9321426 DOI: 10.1371/journal.pone.0271975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Accepted: 07/11/2022] [Indexed: 11/18/2022] Open

Abstract

Background

The selection of the appropriate species is one of the key issues in experimental medicine. Bile duct ligation is the mostly used experimental model in rodents to explore special aspects of occlusive cholestasis. We aimed to clarify if rats or mice are suitable for the same or different aspects in cholestasis research.

Methods

We induced biliary occlusion by ligation and transection of the common bile duct (tBDT) in rats and mice (each n = 25). Recovery from surgical stress was assessed by daily scoring (stress score, body weight). At five different time points (days 1, 3, 7, 14, 28 after tBDT) we investigated hepatic morphometric and architectural alterations (Haematoxylin-Eosin staining, Elastica van Gieson staining) and the proliferative activities of parenchyma cells (Bromodeoxyuridine staining); as well as established systemic markers for liver synthesis, hepatocellular damage and renal dysfunction.

Results

We found substantial differences regarding survival (rats: 100%, 25/25 vs. mice 92%, 22/25, p = 0.07) and body weight gain (p<0.05 at postoperative days 14 and 28 (POD)). Rats showed a faster and progressive hepatobiliary remodelling than mice (p<0.05 at POD 7+14+28), resulting in: i) stronger relative loss of hepatocellular mass (rats by 31% vs. mice by 15% until POD 28; p<0.05 at POD 7+14+28); ii) rapidly progressing liver fibrosis (p<0.05 at POD 14); iii) a faster and stronger proliferative response of parenchyma cells (hepatocytes: p<0.05 at POD 1+14+18; cholangiocytes: p<0.05 at POD 1+3+7+28); and iv) only tiny bile infarcts compared to mice (p<0.05 at POD 1+3+7+14). Both species showed comparable elevated markers of hepatocellular damage and serum bilirubin.

Conclusion

The key difference between rats and mice are the severity and dynamics of histological alterations, possibly accounting for their different susceptibilities for (septic) complications with low survival (mice).

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Substance P Hinders Bile Acid-Induced Hepatocellular Injury by Modulating Oxidative Stress and Inflammation. Antioxidants (Basel) 2022;11:antiox11050920. [PMID: 35624784 PMCID: PMC9137937 DOI: 10.3390/antiox11050920] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 05/05/2022] [Accepted: 05/06/2022] [Indexed: 11/17/2022] Open

Richter B, Zafarnia S, Gremse F, Kießling F, Scheuerlein H, Settmacher U, Dahmen U. Corrosion Cast and 3D Reconstruction of the Murine Biliary Tree After Biliary Obstruction: Quantitative Assessment and Comparison With 2D Histology. J Clin Exp Hepatol 2022;12:755-766. [PMID: 35677523 PMCID: PMC9168744 DOI: 10.1016/j.jceh.2021.12.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 12/10/2021] [Indexed: 12/12/2022] Open

Abstract

Background

Obstructive cholestasis can lead to significant alterations of the biliary tree depending on the extent and duration of the biliary occlusion. Current experimental studies reported about advanced techniques for corrosion cast and 3D reconstruction (3D-reco) visualizing delicate microvascular structures in animals. We compared these two different techniques for visualization and quantitative assessment of the obstructed murine biliary tree with classical 2D histology.

Methods

Male mice (n = 36) were allocated to 3 different experiments. In experiments 1 and 2, we injected two different media (Microfil© for 3D-reco, MV; Batson's No.17 for corrosion cast, CC) into the extrahepatic bile duct. In experiment 3 we sampled liver tissue for 2D histology (HE, BrdU). Time points of interest were days 1, 3, 5, 7, 14, and 28 after biliary occlusion. We used different types of software for quantification of the different samples: IMALYTICS Preclinical for 3D scans (MV); NDP.view2 for the digital photography of CC; HistoKat software for 2D histology.

Results

We achieved samples in 75% of the animals suitable for evaluation (MV and CC, each with 9/12). Contrasting of terminal bile ducts (4th order of branches) was achieved with either technique. MV permitted a fast 3D-reco of the hierarchy of the biliary tree, including the 3rd and 4th order of branches in almost all samples (8/9 and 6/9). CC enabled focused evaluation of the hierarchy of the biliary tree, including the 4th to 5th order of branches in almost all samples (9/9 and 8/9). In addition, we detected dense meshes of the smallest bile ducts in almost all CC samples (8/9). MV and CC allowed a quantitative assessment of anatomical details of the 3rd and 4th order branches of almost every sample. The 2D histology identified different kinetics and areas of proliferation of hepatocytes and cholangiocytes. Complementary usage of 3D-reco, corrosion casting and 2D histology matched dense meshes of small bile ducts with areas of intensive proliferative activity of cholangiocytes as periportal proliferative areas of 4th and 5th order branches (∼terminal bile ducts and bile ductules) matched with its morphological information the matching assessment of areas with increased proliferative activity (BrdU) and a partial quantification of the characteristics of the 4th order branches of the biliary tree.

Conclusion

The 3D-reco and corrosion casting of the murine biliary tree are feasible and provide a straightforward, robust, and reliable (and more economical) procedure for the visualization and quantitative assessment of architectural alterations, in comparative usage with the 2D histology.

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Lin S, Araujo C, Hall A, Kumar R, Phillips A, Hassan M, Engelmann C, Quaglia A, Jalan R. Prognostic Role of Liver Biopsy in Patients With Severe Indeterminate Acute Hepatitis. Clin Gastroenterol Hepatol 2022;20:1130-1141.e7. [PMID: 34389485 DOI: 10.1016/j.cgh.2021.08.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 07/15/2021] [Accepted: 08/02/2021] [Indexed: 02/06/2023]

Affiliation(s)

Su Lin Liver Failure Group, Institute for Liver and Digestive Health, Division of Medicine, Royal Free Hospital, University College London Medical School, London, United Kingdom; Hepatology Research Institute, Department of Hepatology, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
Catarina Araujo Department of Cellular Pathology, Royal Free Hospital, London, United Kingdom; Anatomical-Pathology Department, Centro Hospitalar Universitário Lisboa Central, Lisbon, Portugal
Andrew Hall Liver Failure Group, Institute for Liver and Digestive Health, Division of Medicine, Royal Free Hospital, University College London Medical School, London, United Kingdom; Department of Cellular Pathology, Royal Free Hospital, London, United Kingdom; Sheila Sherlock Liver Center, Royal Free London NHS Foundation Trust, London, United Kingdom
Rahul Kumar Liver Failure Group, Institute for Liver and Digestive Health, Division of Medicine, Royal Free Hospital, University College London Medical School, London, United Kingdom; Department of Gastroenterology and Hepatology, Duke-NUS Academic Medical Centre, Changi General Hospital, Singapore
Alexandra Phillips Liver Failure Group, Institute for Liver and Digestive Health, Division of Medicine, Royal Free Hospital, University College London Medical School, London, United Kingdom
Mohsin Hassan Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Berlin, Germany
Cornelius Engelmann Liver Failure Group, Institute for Liver and Digestive Health, Division of Medicine, Royal Free Hospital, University College London Medical School, London, United Kingdom; Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Berlin, Germany; Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany; Berlin Institute of Health, Berlin, Germany
Alberto Quaglia Department of Cellular Pathology, UCL Cancer Institute, Royal Free Hospital, London, United Kingdom
Rajiv Jalan Liver Failure Group, Institute for Liver and Digestive Health, Division of Medicine, Royal Free Hospital, University College London Medical School, London, United Kingdom; European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain.

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Richter B, Sänger C, Mussbach F, Scheuerlein H, Settmacher U, Dahmen U. The Interplay Between Biliary Occlusion and Liver Regeneration: Repeated Regeneration Stimuli Restore Biliary Drainage by Promoting Hepatobiliary Remodeling in a Rat Model. Front Surg 2022;9:799669. [PMID: 35548189 PMCID: PMC9081651 DOI: 10.3389/fsurg.2022.799669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 03/21/2022] [Indexed: 12/04/2022] Open

Abstract

Background and Aims

Patients with malignant biliary obstruction do not seem to benefit from “two-stage hepatectomy” due to an impairment of liver regeneration. We designed a novel model of “repeated regeneration stimuli” in rats mimicking a “two-stage hepatectomy” with selective or complete biliary occlusion mimicking Klatskin tumors III° or IV°. Using this new model, we wanted to investigate (1) the impact of preexistent cholestasis of different extent on the time course of liver regeneration and (2) the dynamics of hepatobiliary remodeling under regeneration conditions.

Materials and Methods

Rats were subjected to a sequence of three operations: surgical induction of biliary occlusion, followed by “repeated regeneration stimuli” consisting of ligation of the left branch of the portal vein (supplying 70% of the liver volume, sPVL) as first stage and a 70%-hepatectomy (70%PHx) as second stage. Biliary occlusion (1st procedure) was induced by ligating and transection of either the common (100%, tBDT) or the left bile duct (70%, sBDT). A sham operation without ligating the bile duct was performed as control (0%, Sham). Two weeks later, on day 14 (POD14), the sPVL (2nd procedure) was performed. Another week later (POD 21), the 70%PHx (3rd procedure) took place and animals were observed for 1 week (POD 28). The first experiment (n = 45 rats) was dedicated to investigating liver regeneration (hypertrophy/atrophy), proliferative activity and hepatobiliary histomorphology (2D-histology: HE, BrdU) in the future liver remnant (FLR). The second experiment (n = 25 rats) was performed to study the dynamics of hepatobiliary remodeling in livers with different regenerative pressure (tBDT only POD21 vs. tBDT only POD 28 vs. tBDT + sPVL vs. tBDT + 70%PHx vs. tBDT + sPVL + 70%PHx) using μCT scans of explanted livers.

Results

Effect of biliary occlusion

Total biliary occlusion (tBDT) led to a 2.4-fold increase in whole liver volume due to severe biliary proliferation within 14 days. In contrast, partial biliary occlusion (sBDT) caused only a volume gain of the obstructed liver lobes due to biliary proliferates, resulting in a minor increase of total liver volume (1.7-fold) without an increase in bilirubin levels.

Liver regeneration and atrophy

As expected, sPVL caused substantial volume gain (tBDT: 3-fold; sBDT: 2.8-fold; Sham 2.8-fold) of FLR and a substantial volume loss (tBDT: 0.9-fold; sBDT: 0.6-fold; Sham: 0.4-fold) of the portally deprived “future resected lobes” compared to the preoperative liver volume. The subsequent 70%PHx promoted a further volume gain of the FLR in all groups (tBDT: 4-fold; sBDT: 3-fold; Sham 3-fold compared to original volume) until POD 28. Hepatobiliary remodeling: After tBDT, we identified histologically three phases of hepatobiliary remodeling in the FLR. Following tBDT, biliary proliferates developed, replacing about 15% of the hepatocellular tissue. After sPVL we found incomplete restoration of the hepatocellular tissue with a visible reduction of the biliary proliferates. The 70%PHx led to an almost complete recovery of the hepatocellular tissue in the FLR with a nearly normal liver architecture. In contrast, after sBDT and Sham we observed a near normal liver morphology in the FLR at all time points. CT-scanning of the explanted livers and subsequent 3D reconstruction visualized the development of extrahepatic biliary collaterals. Collaterals were detected in 0/5 cases 1 week after sPVL (first regeneration stimulus), and in even more cases (3/5) 1 week after the 70%PHx (second regeneration stimulus). Histological workup identified the typical biliary cuboid epithelium as inner lining of the collaterals and peribiliary glands.

Conclusion

Liver volume of the FLR increased in cholestatic rats mainly due to biliary proliferates. Application of repeated regeneration stimuli in the style of a “two-stage hepatectomy” promoted almost full restoration of hepatocellular tissue and architecture in the FLR by reestablishing biliary drainage via formation of biliary collaterals. Further exploration of the dynamics in hepatobiliary modeling using this model might help to better understand the underlying mechanism.

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Harnisch LO, Baumann S, Mihaylov D, Kiehntopf M, Bauer M, Moerer O, Quintel M. Biomarkers of Cholestasis and Liver Injury in the Early Phase of Acute Respiratory Distress Syndrome and Their Pathophysiological Value. Diagnostics (Basel) 2021;11:diagnostics11122356. [PMID: 34943592 PMCID: PMC8699895 DOI: 10.3390/diagnostics11122356] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/17/2021] [Accepted: 12/13/2021] [Indexed: 11/16/2022] Open

Abstract

Background: Impaired liver function and cholestasis are frequent findings in critically ill patients and are associated with poor outcomes. We tested the hypothesis that hypoxic liver injury and hypoxic cholangiocyte injury are detectable very early in patients with ARDS, may depend on the severity of hypoxemia, and may be aggravated by the use of rescue therapies (high PEEP level and prone positioning) but could be attenuated by extracorporeal membrane oxygenation (ECMO). Methods: In 70 patients with ARDS, aspartate-aminotransferase (AST), alanin-aminotransferase (ALT) and gamma glutamyltransferase (GGT) were measured on the day of the diagnosis of ARDS and three more consecutive days (day 3, day 5, day 10), total bile acids were measured on day 0, 3, and 5. Results: AST levels increased on day 0 and remained constant until day 5, then dropped to normal on day 10 (day 0: 66.5 U/l; day 3: 60.5 U/l; day 5: 63.5 U/l, day 10: 32.1 U/l), ALT levels showed the exact opposite kinetic. GGT was already elevated on day 0 (91.5 U/l) and increased further throughout (day 3: 163.5 U/l, day 5: 213 U/l, day 10: 307 U/l), total bile acids levels increased significantly from day 0 to day 3 (p = 0.019) and day 0 to day 5 (p < 0.001), but not between day 3 and day 5 (p = 0.217). Total bile acids levels were significantly correlated to GGT on day 0 (p < 0.001), day 3 (p = 0.02), and in a trend on day 5 (p = 0.055). PEEP levels were significantly correlated with plasma levels of AST (day 3), ALT (day 5) and GGT (day 10). Biomarker levels were not associated with the use of ECMO, prone position, the cause of ARDS, and paO₂. Conclusions: We found no evidence of hypoxic liver injury or hypoxic damage to cholangiocytes being caused by the severity of hypoxemia in ARDS patients during the very early phase of the disease. Additionally, mean PEEP level, prone positioning, and ECMO treatment did not have an impact in this regard. Nevertheless, GGT levels were elevated from day zero and rising, this increase was not related to paO₂, prone position, ECMO treatment, or mean PEEP, but correlated to total bile acid levels.

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Wang Y, Chen B, Xiao C, Yu J, Bu X, Jiang F, Ding W, Ge Z. Effect of miR-183-5p on Cholestatic Liver Fibrosis by Regulating Fork Head Box Protein O1 Expression. Front Physiol 2021;12:737313. [PMID: 34867446 PMCID: PMC8639207 DOI: 10.3389/fphys.2021.737313] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 10/11/2021] [Indexed: 11/13/2022] Open

Abstract

Liver fibrosis is a common pathological feature of end-stage liver disease and has no effective treatment. MicroRNAs (miRNAs) have been found to modulate gene expression in liver disease. But the potential role of miRNA in hepatic fibrosis is still unclear. The objective of this research is to study the potential mechanism and biological function of miR-183-5p in liver fibrosis. In this study, we used high-throughput sequencing to find that miR-183-5p is upregulated in human fibrotic liver tissues. In addition, miR-183-5p was upregulated both in rat liver fibrosis tissue induced by bile-duct ligation (BDL) and activated LX-2 cells (human hepatic stellate cell line) according to the result of quantitative real-time PCR (RT-qPCR). Moreover, the inhibition of miR-183-5p alleviated liver fibrosis, decreased the fibrotic biomarker levels in vitro and in vivo, and led toLX-2 cell proliferation inhibition and, apoptosis induction. The result of dual-luciferase assay revealed that miR-183-5p suppressed fork head box protein O1 (FOXO1) expression by binding to its 3'UTR directly. Next, we used lentivirus to overexpress FOXO1 in LX-2 cells, and we found that overexpression of FOXO1 reversed the promotion of miR-183-5p on liver fibrosis, reducing the fibrotic biomarker levels inLX-2 cells, inhibitingLX-2 cell proliferation, and promoting apoptosis. Furthermore, overexpression of FOXO1 prevented the activation of the transforming growth factor (TGF)-β signaling pathway in TGF-β1-induced LX-2 cells according to the result of western blotting. In conclusion, the findings showed thatmiR-183-5p might act as a key regulator of liver fibrosis, and miR-183-5p could promote cholestatic liver fibrosis by inhibiting FOXO1 expression through the TGF-β signaling pathway. Thus, inhibition of miR-183-5pmay be a new way to prevent and improve liver fibrosis.

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Starosta RT, Siebert M, Vairo FPE, Costa BLDL, Ponzoni CT, Schwartz IVD, Cerski CTS. Histomorphometric analysis of liver biopsies of treated patients with Gaucher disease type 1. AUTOPSY AND CASE REPORTS 2021;11:e2021306. [PMID: 34458174 PMCID: PMC8387085 DOI: 10.4322/acr.2021.306] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 06/15/2021] [Indexed: 01/12/2023] Open

Mugarab Samedi V, Rahimi M, Kalaniti K, Lyon M, Daspal S. Rainbow of colors: Inspissated bile syndrome secondary to hemolytic disease of the newborn and concomitant serum dynamics. SAGE Open Med Case Rep 2021;9:2050313X211025435. [PMID: 34188935 PMCID: PMC8212369 DOI: 10.1177/2050313x211025435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 05/27/2021] [Indexed: 11/17/2022] Open

High Rate of Gastrointestinal Bleeding in Patients with Secondary Sclerosing Cholangitis in Critically Ill Patients (SC-CIP). J Clin Med 2021;10:jcm10091925. [PMID: 33946877 PMCID: PMC8125451 DOI: 10.3390/jcm10091925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 04/21/2021] [Accepted: 04/27/2021] [Indexed: 11/26/2022] Open

Augmenter of Liver Regeneration (ALR) regulates bile acid synthesis and attenuates bile acid-induced apoptosis via glycogen synthase kinase-3β (GSK-3β) inhibition. Exp Cell Res 2020;397:112343. [PMID: 33132196 DOI: 10.1016/j.yexcr.2020.112343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 10/19/2020] [Accepted: 10/23/2020] [Indexed: 11/23/2022]

Ali O, Szabó-Fodor J, Fébel H, Mézes M, Balogh K, Glávits R, Kovács M, Zantomasi A, Szabó A. Porcine Hepatic Response to Fumonisin B₁ in a Short Exposure Period: Fatty Acid Profile and Clinical Investigations. Toxins (Basel) 2019;11:E655. [PMID: 31717687 PMCID: PMC6891595 DOI: 10.3390/toxins11110655] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 11/06/2019] [Accepted: 11/08/2019] [Indexed: 12/13/2022] Open

Mamede KM, Sant'anna LB. Antifibrotic effects of total or partial application of amniotic membrane in hepatic fibrosis. AN ACAD BRAS CIENC 2019;91:e20190220. [PMID: 31531535 DOI: 10.1590/0001-3765201920190220] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Accepted: 07/05/2019] [Indexed: 12/24/2022] Open

Van Haele M, Snoeck J, Roskams T. Human Liver Regeneration: An Etiology Dependent Process. Int J Mol Sci 2019;20:ijms20092332. [PMID: 31083462 PMCID: PMC6539121 DOI: 10.3390/ijms20092332] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Revised: 05/06/2019] [Accepted: 05/09/2019] [Indexed: 02/07/2023] Open

Pradhan-Sundd T, Monga SP. Blood-Bile Barrier: Morphology, Regulation, and Pathophysiology. Gene Expr 2019;19:69-87. [PMID: 30646969 PMCID: PMC6466181 DOI: 10.3727/105221619x15469715711907] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]

Behairy BES, Konswa HAA, Ahmed HT, El-Azab DS, Adawy NM, Sira AM. Serum ferritin in neonatal cholestasis: A specific and active molecule or a non-specific bystander marker? Hepatobiliary Pancreat Dis Int 2019;18:173-180. [PMID: 30833173 DOI: 10.1016/j.hbpd.2019.02.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Accepted: 02/16/2019] [Indexed: 02/05/2023]

Abstract

BACKGROUND

Serum ferritin (SF) and consequently hepatic iron have long been considered important in liver fibrosis progression. They have been studied in different liver diseases with no previous reports in neonatal cholestasis (NC). This study aimed to measure SF in different etiologies of NC and investigate its relation to hepatic iron and fibrosis.

METHODS

SF was measured in 75 infants, including 50 with NC and 25 with sepsis. SF was compared between these two groups. Biochemical parameters, hepatic iron grades, and liver fibrosis and other histopathological characteristics and correlated with SF were assessed in NC group. Finally, a comparison between intrahepatic cholestasis and obstructive etiology was performed.

RESULTS

SF was elevated in NC (1598 ± 2405 ng/mL) with no significant difference from those with sepsis (P = 0.445). NC and sepsis constituted augmenting factors leading to more elevation of SF (2589 ± 3511 ng/mL). SF was significantly correlated with hepatic iron grades (r = 0.536, P < 0.0001) and a cut-off value of 803.5 ng/mL can predict higher grades (≥ grade 3) of iron deposition with sensitivity of 100%, specificity of 70% and accuracy of 85%. Moreover, SF was significantly higher (P < 0.0001) in those with intrahepatic cholestasis (2602 ± 3154 ng/mL) and their prevalent pathological findings of giant cell transformation (P = 0.009) and hepatocyte swelling (P = 0.023) than those with obstructive etiology (672 ± 566 ng/mL) and their prevalent pathological findings of ductular proliferation (P = 0.003) and bile plugs (P = 0.002). SF was unrelated to the grade of liver fibrosis (P = 0.058).

CONCLUSIONS

SF is non-specifically elevated in NC, with positive correlation to hepatic iron grades. SF ≥ 803.5 ng/mL can predict higher grades (≥ grade 3) of hepatic iron. However, an active role of increased SF and hepatic iron in disease progression remains questionable.

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Wang C, Cheng Y, Zhang X, Li N, Zhang L, Wang S, Tong X, Xu Y, Chen GQ, Cheng S, Fan X, Liu J. Vacuolar Protein Sorting 33B Is a Tumor Suppressor in Hepatocarcinogenesis. Hepatology 2018;68:2239-2253. [PMID: 29729199 DOI: 10.1002/hep.30077] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Accepted: 05/20/2018] [Indexed: 12/11/2022]

Affiliation(s)

Conghui Wang Department of Biochemistry and Molecular Cell Biology, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Yuqiang Cheng Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
Xiuping Zhang Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
Nan Li Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
Lin Zhang Department of Biochemistry and Molecular Cell Biology, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Shengdian Wang Key Laboratory of Infection and Immunity, Institute of Biophysics, University of Chinese Academy of Sciences, Beijing, China
Xuemei Tong Department of Biochemistry and Molecular Cell Biology, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Ying Xu Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Guo-Qiang Chen Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Shuqun Cheng Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
Xuemei Fan Department of Biochemistry and Molecular Cell Biology, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Junling Liu Department of Biochemistry and Molecular Cell Biology, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Collaborative Innovation Center of Hematology, Shanghai Jiao Tong University School of Medicine, Shanghai, China

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Cai FF, Wu R, Song YN, Xiong AZ, Chen XL, Yang MD, Yang L, Hu Y, Sun MY, Su SB. Yinchenhao Decoction Alleviates Liver Fibrosis by Regulating Bile Acid Metabolism and TGF-β/Smad/ERK Signalling Pathway. Sci Rep 2018;8:15367. [PMID: 30337590 PMCID: PMC6194075 DOI: 10.1038/s41598-018-33669-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Accepted: 07/31/2018] [Indexed: 12/12/2022] Open

Richter B, Khodaverdi S, Bechstein WO, Gutt CN, Krähenbühl L, Schmandra TC. Reversible biliary occlusion in a small animal model: first description of a new technique. Innov Surg Sci 2018;3:261-270. [PMID: 31579790 PMCID: PMC6604588 DOI: 10.1515/iss-2018-0021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Accepted: 07/17/2018] [Indexed: 12/15/2022] Open

Pradhan-Sundd T, Zhou L, Vats R, Jiang A, Molina L, Singh S, Poddar M, Russell JM, Stolz DB, Oertel M, Apte U, Watkins S, Ranganathan S, Nejak-Bowen KN, Sundd P, Monga SP. Dual catenin loss in murine liver causes tight junctional deregulation and progressive intrahepatic cholestasis. Hepatology 2018;67:2320-2337. [PMID: 29023813 PMCID: PMC5893443 DOI: 10.1002/hep.29585] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Revised: 09/03/2017] [Accepted: 10/04/2017] [Indexed: 01/04/2023]

Abstract

UNLABELLED

β-Catenin, the downstream effector of the Wnt signaling, plays important roles in hepatic development, regeneration, and tumorigenesis. However, its role at hepatocyte adherens junctions (AJ) is relatively poorly understood, chiefly due to spontaneous compensation by γ-catenin. We simultaneously ablated β- and γ-catenin expression in mouse liver by interbreeding β-catenin-γ-catenin double-floxed mice and Alb-Cre transgenic mice. Double knockout mice show failure to thrive, impaired hepatocyte differentiation, cholemia, ductular reaction, progressive cholestasis, inflammation, fibrosis, and tumorigenesis, which was associated with deregulation of tight junctions (TJ) and bile acid transporters, leading to early morbidity and mortality, a phenotype reminiscent of progressive familial intrahepatic cholestasis (PFIC). To address the mechanism, we specifically and temporally eliminated both catenins from hepatocytes using adeno-associated virus 8 carrying Cre-recombinase under the thyroid-binding globulin promoter (AAV8-TBG-Cre). This led to a time-dependent breach of the blood-biliary barrier associated with sequential disruption of AJ and TJ verified by ultrastructural imaging and intravital microscopy, which revealed unique paracellular leaks around individual hepatocytes, allowing mixing of blood and bile and leakage of blood from one sinusoid to another. Molecular analysis identified sequential losses of E-cadherin, occludin, claudin-3, and claudin-5 due to enhanced proteasomal degradation, and of claudin-2, a β-catenin transcriptional target, which was also validated in vitro.

CONCLUSION

We report partially redundant function of catenins at AJ in regulating TJ and contributing to the blood-biliary barrier. Furthermore, concomitant hepatic loss of β- and γ-catenin disrupts structural and functional integrity of AJ and TJ via transcriptional and posttranslational mechanisms. Mice with dual catenin loss develop progressive intrahepatic cholestasis, providing a unique model to study diseases such as PFIC. (Hepatology 2018;67:2320-2337).

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Affiliation(s)

Tirthadipa Pradhan-Sundd Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA
Lili Zhou Dept. of General Surgery, School of Medicine, Xi'an Jiaotong University, China
Ravi Vats Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA
An Jiang Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA
Laura Molina Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA
Sucha Singh Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA
Minakshi Poddar Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA
Jacquelyn M Russell Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA
Donna B Stolz Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA,Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA
Michael Oertel Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA,Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA
Udayan Apte Department of Pharmacology, Toxicology and Therapeutics, Kansas University Medical Center, Kansas City, KS
Simon Watkins Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA,Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA
Sarangarajan Ranganathan Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA,Children's Hospital of Pittsburgh, Pittsburgh, PA
Kari N. Nejak-Bowen Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA,Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA
Prithu Sundd Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA,Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA,Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA
Satdarshan Pal Monga Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA,Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA,Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA,Address Correspondence to: Satdarshan P. S. Monga, MD, FAASLD., Endowed Chair for Experimental Pathology, Director: Pittsburgh Liver Research Center, Professor of Pathology (EP) & Medicine (Gastroenterology, Hepatology & Nutrition), Assistant Dean and Co-Director: Medical Scientist Training Program, University of Pittsburgh, School of Medicine, 200 Lothrop Street S-422 BST, Pittsburgh, PA 15261, Tel: (412) 648-9966; Fax: (412) 648-1916;

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Prigge JR, Coppo L, Martin SS, Ogata F, Miller CG, Bruschwein MD, Orlicky DJ, Shearn CT, Kundert JA, Lytchier J, Herr AE, Mattsson Å, Taylor MP, Gustafsson TN, Arnér ESJ, Holmgren A, Schmidt EE. Hepatocyte Hyperproliferation upon Liver-Specific Co-disruption of Thioredoxin-1, Thioredoxin Reductase-1, and Glutathione Reductase. Cell Rep 2018;19:2771-2781. [PMID: 28658624 PMCID: PMC5730093 DOI: 10.1016/j.celrep.2017.06.019] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Revised: 05/16/2017] [Accepted: 06/02/2017] [Indexed: 12/21/2022] Open

Affiliation(s)

Justin R Prigge Microbiology & Immunology, Montana State University, Bozeman, MT 59718, USA
Lucia Coppo Division of Biochemistry, Medical Biochemistry & Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden
Sebastin S Martin Division of Biochemistry, Medical Biochemistry & Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden
Fernando Ogata Division of Biochemistry, Medical Biochemistry & Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden
Colin G Miller Microbiology & Immunology, Montana State University, Bozeman, MT 59718, USA
Michael D Bruschwein Microbiology & Immunology, Montana State University, Bozeman, MT 59718, USA
David J Orlicky Department of Pathology, University of Colorado Anschutz Medical Center, Denver, CO 80045, USA
Colin T Shearn Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Center, Denver, CO 80045, USA
Jean A Kundert Microbiology & Immunology, Montana State University, Bozeman, MT 59718, USA
Julia Lytchier Division of Biochemistry, Medical Biochemistry & Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden
Alix E Herr Microbiology & Immunology, Montana State University, Bozeman, MT 59718, USA
Åse Mattsson Division of Biochemistry, Medical Biochemistry & Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden
Matthew P Taylor Microbiology & Immunology, Montana State University, Bozeman, MT 59718, USA
Tomas N Gustafsson Division of Biochemistry, Medical Biochemistry & Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Clinical Microbiology, Clinical Bacteriology, Sunderby Research Unit, Umeå University, 901 85 Umeå, Sweden
Elias S J Arnér Division of Biochemistry, Medical Biochemistry & Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden
Arne Holmgren Division of Biochemistry, Medical Biochemistry & Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden
Edward E Schmidt Microbiology & Immunology, Montana State University, Bozeman, MT 59718, USA.

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Chenodeoxycholic acid activates NLRP3 inflammasome and contributes to cholestatic liver fibrosis. Oncotarget 2018;7:83951-83963. [PMID: 27924062 PMCID: PMC5356637 DOI: 10.18632/oncotarget.13796] [Citation(s) in RCA: 103] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2016] [Accepted: 11/22/2016] [Indexed: 12/20/2022] Open

Mitochondrial Mutations in Cholestatic Liver Disease with Biliary Atresia. Sci Rep 2018;8:905. [PMID: 29343773 PMCID: PMC5772057 DOI: 10.1038/s41598-017-18958-8] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Accepted: 12/19/2017] [Indexed: 12/25/2022] Open

Crawford JM, Bioulac-Sage P, Hytiroglou P. Structure, Function, and Responses to Injury. MACSWEEN'S PATHOLOGY OF THE LIVER 2018:1-87. [DOI: 10.1016/b978-0-7020-6697-9.00001-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]

Lin SY, Wang YY, Chen WY, Liao SL, Chou ST, Yang CP, Chen CJ. Hepatoprotective activities of rosmarinic acid against extrahepatic cholestasis in rats. Food Chem Toxicol 2017;108:214-223. [PMID: 28789951 DOI: 10.1016/j.fct.2017.08.005] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2017] [Revised: 06/30/2017] [Accepted: 08/04/2017] [Indexed: 12/29/2022]

Obayashi J, Kawaguchi K, Manabe S, Nagae H, Wakisaka M, Koike J, Takagi M, Kitagawa H. Prognostic factors indicating survival with native liver after Kasai procedure for biliary atresia. Pediatr Surg Int 2017;33:1047-1052. [PMID: 28852838 DOI: 10.1007/s00383-017-4135-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/01/2017] [Indexed: 02/06/2023]

Sant'Anna L, Brito F, Barja P, Nicodemo M. Long-term effects of human amniotic membrane in a rat model of biliary fibrosis. Braz J Med Biol Res 2017;50:e5692. [PMID: 28678914 PMCID: PMC5496151 DOI: 10.1590/1414-431x20175692] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Accepted: 04/18/2017] [Indexed: 12/11/2022] Open

Gupta K, Li Q, Fan JJ, Fong ELS, Song Z, Mo S, Tang H, Ng IC, Ng CW, Pawijit P, Zhuo S, Dong CY, Low BC, Wee A, Dan YY, Kanchanawong P, So P, Viasnoff V, Yu H. Actomyosin contractility drives bile regurgitation as an early response during obstructive cholestasis. J Hepatol 2017;66:1231-1240. [PMID: 28189756 DOI: 10.1016/j.jhep.2017.01.026] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2016] [Revised: 01/10/2017] [Accepted: 01/29/2017] [Indexed: 01/06/2023]

Abstract

BACKGROUND & AIMS

A wide range of liver diseases manifest as biliary obstruction, or cholestasis. However, the sequence of molecular events triggered as part of the early hepatocellular homeostatic response in obstructive cholestasis is poorly elucidated. Pericanalicular actin is known to accumulate during obstructive cholestasis. Therefore, we hypothesized that the pericanalicular actin cortex undergoes significant remodeling as a regulatory response to obstructive cholestasis.

METHODS

In vivo investigations were performed in a bile duct-ligated mouse model. Actomyosin contractility was assessed using sandwich-cultured rat hepatocytes transfected with various fluorescently labeled proteins and pharmacological inhibitors of actomyosin contractility.

RESULTS

Actomyosin contractility induces transient deformations along the canalicular membrane, a process we have termed inward blebbing. We show that these membrane intrusions are initiated by local ruptures in the pericanalicular actin cortex; and they typically retract following repair by actin polymerization and actomyosin contraction. However, above a certain osmotic pressure threshold, these inward blebs pinch away from the canalicular membrane into the hepatocyte cytoplasm as large vesicles (2-8μm). Importantly, we show that these vesicles aid in the regurgitation of bile from the bile canaliculi.

CONCLUSION

Actomyosin contractility induces the formation of bile-regurgitative vesicles, thus serving as an early homeostatic mechanism against increased biliary pressure during cholestasis.

LAY SUMMARY

Bile canaliculi expand and contract in response to the amount of secreted bile, and resistance from the surrounding actin bundles. Further expansion due to bile duct blockade leads to the formation of inward blebs, which carry away excess bile to prevent bile build up in the canaliculi.

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Affiliation(s)

Kapish Gupta Mechanobiology Institute, National University of Singapore, Singapore
Qiushi Li Mechanobiology Institute, National University of Singapore, Singapore; National University of Singapore Research Institute, Singapore
Jun Jun Fan Institute of Bioengineering and Nanotechnology, Agency for Science, Technology and Research (A*STAR), Singapore; BioSyM, Singapore-MIT Alliance for Research and Technology, Singapore; Department of Orthopaedics, Xijing Hospital, Fourth Military Medical University, China
Eliza Li Shan Fong Department of Physiology, National University of Singapore, Singapore; Department of Biomedical Engineering, National University of Singapore, Singapore
Ziwei Song Institute of Bioengineering and Nanotechnology, Agency for Science, Technology and Research (A*STAR), Singapore
Shupei Mo Institute of Bioengineering and Nanotechnology, Agency for Science, Technology and Research (A*STAR), Singapore
Haoyu Tang Mechanobiology Institute, National University of Singapore, Singapore
Inn Chuan Ng Department of Physiology, National University of Singapore, Singapore
Chan Way Ng Department of Physiology, National University of Singapore, Singapore
Pornteera Pawijit Department of Physiology, National University of Singapore, Singapore; NUS Graduate School of Integrative Sciences and Engineering, National University of Singapore, Singapore
Shuangmu Zhuo BioSyM, Singapore-MIT Alliance for Research and Technology, Singapore; Fujian Normal University, Fuzhou, Fujian, China
Chen-Yuan Dong Department of Physics, National Taiwan University, Taiwan
Boon Chuan Low Mechanobiology Institute, National University of Singapore, Singapore; Department of Biological Sciences, National University of Singapore, Singapore
Aileen Wee Department of Pathology, National University of Singapore, Singapore
Yock Young Dan Division of Gastroenterology and Hepatology, National University Hospital, Singapore
Pakorn Kanchanawong Mechanobiology Institute, National University of Singapore, Singapore; Department of Biomedical Engineering, National University of Singapore, Singapore
Peter So BioSyM, Singapore-MIT Alliance for Research and Technology, Singapore
Virgile Viasnoff Mechanobiology Institute, National University of Singapore, Singapore; CNRS UMI3639, Singapore
Hanry Yu Mechanobiology Institute, National University of Singapore, Singapore; Institute of Bioengineering and Nanotechnology, Agency for Science, Technology and Research (A*STAR), Singapore; BioSyM, Singapore-MIT Alliance for Research and Technology, Singapore; Department of Physiology, National University of Singapore, Singapore; Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China.

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Castro Ghizoni CV, Arssufi Ames AP, Lameira OA, Bersani Amado CA, Sá Nakanishi AB, Bracht L, Marçal Natali MR, Peralta RM, Bracht A, Comar JF. Anti‐Inflammatory and Antioxidant Actions of Copaiba Oil Are Related to Liver Cell Modifications in Arthritic Rats. J Cell Biochem 2017;118:3409-3423. [DOI: 10.1002/jcb.25998] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Accepted: 03/17/2017] [Indexed: 01/15/2023]

Wang YY, Lin SY, Chen WY, Liao SL, Wu CC, Pan PH, Chou ST, Chen CJ. Glechoma hederacea extracts attenuate cholestatic liver injury in a bile duct-ligated rat model. JOURNAL OF ETHNOPHARMACOLOGY 2017;204:58-66. [PMID: 28416441 DOI: 10.1016/j.jep.2017.04.011] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/07/2017] [Revised: 03/13/2017] [Accepted: 04/13/2017] [Indexed: 06/07/2023]

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE

In traditional Chinese medicine, Glechoma hederacea is frequently prescribed to patients with cholelithiasis, dropsy, abscess, diabetes, inflammation, and jaundice. Polyphenolic compounds are main bioactive components of Glechoma hederacea.

AIM OF THE STUDY

This study was aimed to investigate the hepatoprotective potential of hot water extract of Glechoma hederacea against cholestatic liver injury in rats.

MATERIALS AND METHODS

Cholestatic liver injury was produced by ligating common bile ducts in Sprague-Dawley rats. Saline and hot water extract of Glechoma hederacea were orally administrated using gastric gavages. Liver tissues and bloods were collected and subjected to evaluation using histological, molecular, and biochemical approaches.

RESULTS

Using a rat model of cholestasis caused by bile duct ligation (BDL), daily oral administration of Glechoma hederacea hot water extracts showed protective effects against cholestatic liver injury, as evidenced by the improvement of serum biochemicals, ductular reaction, oxidative stress, inflammation, and fibrosis. Glechoma hederacea extracts alleviated BDL-induced transforming growth factor beta-1 (TGF-β1), connective tissue growth factor, and collagen expression, and the anti-fibrotic effects were accompanied by reductions in α-smooth muscle actin-positive matrix-producing cells and Smad2/3 activity. Glechoma hederacea extracts attenuated BDL-induced inflammatory cell infiltration/accumulation, NF-κB and AP-1 activation, and inflammatory cytokine production. Further studies demonstrated an inhibitory effect of Glechoma hederacea extracts on the axis of high mobility group box-1 (HMGB1)/toll-like receptor-4 (TLR4) intracellular signaling pathways.

CONCLUSIONS

The hepatoprotective, anti-oxidative, anti-inflammatory, and anti-fibrotic effects of Glechoma hederacea extracts seem to be multifactorial. The beneficial effects of daily Glechoma hederacea extracts supplementation were associated with anti-oxidative, anti-inflammatory, and anti-fibrotic potential, as well as down-regulation of NF-κB, AP-1, and TGF-β/Smad signaling, probably via interference with the HMGB1/TLR4 axis.

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Li WK, Li H, Lu YF, Li YY, Fu ZD, Liu J. Atorvastatin alters the expression of genes related to bile acid metabolism and circadian clock in livers of mice. PeerJ 2017;5:e3348. [PMID: 28533986 PMCID: PMC5438592 DOI: 10.7717/peerj.3348] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Accepted: 04/23/2017] [Indexed: 02/06/2023] Open

Joshi N, Kopec AK, Cline-Fedewa H, Luyendyk JP. Lymphocytes contribute to biliary injury and fibrosis in experimental xenobiotic-induced cholestasis. Toxicology 2016;377:73-80. [PMID: 28049044 DOI: 10.1016/j.tox.2016.12.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Revised: 12/20/2016] [Accepted: 12/31/2016] [Indexed: 02/07/2023]

Knockout of microRNA-21 reduces biliary hyperplasia and liver fibrosis in cholestatic bile duct ligated mice. J Transl Med 2016;96:1256-1267. [PMID: 27775690 PMCID: PMC5121007 DOI: 10.1038/labinvest.2016.112] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2016] [Revised: 09/22/2016] [Accepted: 09/26/2016] [Indexed: 12/12/2022] Open

Joshi N, Ray JL, Kopec AK, Luyendyk JP. Dose-dependent effects of alpha-naphthylisothiocyanate disconnect biliary fibrosis from hepatocellular necrosis. J Biochem Mol Toxicol 2016;31:1-7. [PMID: 27605088 DOI: 10.1002/jbt.21834] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2016] [Accepted: 08/10/2016] [Indexed: 12/26/2022]

Mitochondrial gene expression profiles are associated with intrahepatic cholestasis of pregnancy. Placenta 2016;45:16-23. [DOI: 10.1016/j.placenta.2016.07.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Revised: 07/01/2016] [Accepted: 07/08/2016] [Indexed: 12/18/2022]

SantAnna LB, Hage R, Cardoso MAG, Arisawa EAL, Cruz MM, Parolini O, Cargnoni A, SantAnna N. Antifibrotic Effects of Human Amniotic Membrane Transplantation in Established Biliary Fibrosis Induced in Rats. Cell Transplant 2016;25:2245-2257. [PMID: 27480080 DOI: 10.3727/096368916x692645] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open

Abstract

Liver fibrosis is characterized by excessive accumulation of extracellular matrix components in the liver parenchyma that distorts the normal architecture and hepatic function. Progressive fibrosis could end in the advanced stage known as cirrhosis, resulting in the need to resort to liver transplantation. Amniotic membrane (AM) has emerged as an innovative therapeutic approach for chronic liver diseases due to its anti-inflammatory, antiscarring, and wound-healing effects. We have recently shown that AM can be used as a patch on the liver surface at the same time of fibrosis induction, resulting in significantly reduced progression and severity of biliary fibrosis. Here we investigated the effects of human AM on the established rat model of liver fibrosis, induced by the bile duct ligation (BDL). We also explored the effect of AM on the expression of transforming growth factor-1 (TGF-1), the main profibrogenic factor in hepatic fibrosis, and the proinflammatory cytokines, tumor necrosis factor- (TNF-), interleukin-6 (IL-6), and anti-inflammatory cytokine IL-10. Two weeks after BDL, the liver was covered with a fragment of AM or left untreated. Six weeks later, the fibrosis was first assessed by the semiquantitative Knodell and the METAVIR scoring systems and, thereafter, by CellProfiler digital image analysis to quantify the area occupied by collagen deposition, ductular reactions (DRs), activated myofibroblasts, and TGF-1. The hepatic cytokines were determined by ELISA. AM-treated rats showed a significantly lower score compared to the control BDL rats (2.50.9 vs. 3.50.3, respectively; p0.05). The collagen deposition, DRs, number of activated myofibroblasts, and TGF-1 were all reduced to about 50% of levels observed in untreated BDL rats. These findings suggest that AM, when applied as a patch onto the liver surface, is useful for treating well-established cholestatic fibrosis, and the mechanism was partly by means of downregulating the profibrotic factor TGF-1 and IL-6.

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Kirbas A, Biberoglu E, Ersoy AO, Dikmen AU, Koca C, Erdinc S, Uygur D, Caglar T, Biberoglu K. The role of interleukin-17 in intrahepatic cholestasis of pregnancy. J Matern Fetal Neonatal Med 2015;29:977-81. [PMID: 25845273 DOI: 10.3109/14767058.2015.1028354] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]

Kirchner GI, Rümmele P. Update on Sclerosing Cholangitis in Critically Ill Patients. VISZERALMEDIZIN 2015;31:178-84. [PMID: 26468312 PMCID: PMC4569200 DOI: 10.1159/000431031] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]